Description: This is final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.neuropharm.2016.04.027

Abstract: Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT_3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT_3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT_3 receptor-responses were reversibly inhibited by scopolamine with an IC_50 of 2.09 µM. Competitive antagonism was shown by Schild plot (pA_2 = 5.02) and by competition with the 5-HT_3 receptor antagonists [^3H]granisetron (Ki = 6.76 µM) and G-FL (Ki = 4.90 µM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC_50 of 1.74 µM, and competed with G-FL with a Ki of 7.94 µM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 µM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC_50 values found here. It is therefore possible that 5-HT_3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects.

Sponsorship: Our thanks are given to John Peters (University of Dundee) for the 5-HT3A subunit. ML thanks the Swiss National Science Foundation for financial support (SNSF- professorship PP00P2_123536 and PP00P2_146321). AJT thanks the British Heart Foundation for financial support (PG/13/39/30293).